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- PDB-4jr5: Structure-based Identification of Ureas as Novel Nicotinamide Pho... -

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Basic information

Entry
Database: PDB / ID: 4jr5
TitleStructure-based Identification of Ureas as Novel Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors
ComponentsNicotinamide phosphoribosyltransferase
KeywordsTransferase/Transferase inhibitor / Transferase-Transferase inhibitor complex
Function / homology
Function and homology information


nicotinamide phosphoribosyltransferase activity / nicotinamide phosphoribosyltransferase / NAD biosynthesis via nicotinamide riboside salvage pathway / Nicotinamide salvaging / NAD biosynthetic process / : / NPAS4 regulates expression of target genes / BMAL1:CLOCK,NPAS2 activates circadian gene expression / cytokine activity / circadian regulation of gene expression ...nicotinamide phosphoribosyltransferase activity / nicotinamide phosphoribosyltransferase / NAD biosynthesis via nicotinamide riboside salvage pathway / Nicotinamide salvaging / NAD biosynthetic process / : / NPAS4 regulates expression of target genes / BMAL1:CLOCK,NPAS2 activates circadian gene expression / cytokine activity / circadian regulation of gene expression / cell junction / cell-cell signaling / nuclear speck / positive regulation of cell population proliferation / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular exosome / identical protein binding / cytosol
Similarity search - Function
Nicotinamide phosphoribosyl transferase / Nicotinamide phosphoribosyltransferase, N-terminal domain / Nicotinamide phosphoribosyltransferase, N-terminal domain / Nicotinate/nicotinamide phosphoribosyltransferase / Nicotinate phosphoribosyltransferase (NAPRTase) family / Nicotinate phosphoribosyltransferase-like, C-terminal / Aldolase class I / Aldolase-type TIM barrel / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
Chem-1LS / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.906 Å
AuthorsZheng, X. / Bauer, P. / Baumeister, T. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Han, B. / Ho, Y. / Kley, N. / Lin, J. ...Zheng, X. / Bauer, P. / Baumeister, T. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Han, B. / Ho, Y. / Kley, N. / Lin, J. / Reynolds, D.J. / Sharma, G. / Smith, C.C. / Wang, Z. / Dragovich, P.S. / Oh, A. / Wang, W. / Zak, M. / Gunzner-Toste, J. / Zhao, G. / Yuen, P. / Bair, K.W.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (nampt) inhibitors.
Authors: Zheng, X. / Bauer, P. / Baumeister, T. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Han, B. / Ho, Y.C. / Kley, N. / Lin, J. / Reynolds, D.J. / Sharma, G. / Smith, C.C. / Wang, Z. ...Authors: Zheng, X. / Bauer, P. / Baumeister, T. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Han, B. / Ho, Y.C. / Kley, N. / Lin, J. / Reynolds, D.J. / Sharma, G. / Smith, C.C. / Wang, Z. / Dragovich, P.S. / Oh, A. / Wang, W. / Zak, M. / Gunzner-Toste, J. / Zhao, G. / Yuen, P.W. / Bair, K.W.
History
DepositionMar 21, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 8, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2013Group: Database references
Revision 1.2Jul 10, 2013Group: Database references
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nicotinamide phosphoribosyltransferase
B: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,17010
Polymers113,8852
Non-polymers1,2858
Water16,214900
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11660 Å2
ΔGint-58 kcal/mol
Surface area32710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.631, 106.739, 83.174
Angle α, β, γ (deg.)90.00, 96.65, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Nicotinamide phosphoribosyltransferase / NAmPRTase / Nampt / Pre-B-cell colony-enhancing factor 1 / Pre-B cell-enhancing factor / Visfatin


Mass: 56942.375 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NAMPT, PBEF, PBEF1 / Production host: Escherichia coli (E. coli)
References: UniProt: P43490, nicotinamide phosphoribosyltransferase
#2: Chemical ChemComp-1LS / 1-[4-(piperidin-1-ylsulfonyl)phenyl]-3-(pyridin-3-ylmethyl)thiourea


Mass: 390.523 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H22N4O2S2
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 900 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.35 Å3/Da / Density % sol: 47.6 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop
Details: crystals were grown from 0.2uL + 0.2uL drops containing 6mg/mL Nampt, 0.1M Sodium phosphate, 25-29% polyethylene glycol 3350, 0.2M NaCl, 1mM compound, VAPOR DIFFUSION, HANGING DROP, temperature 292K
PH range: 8.6-9.0

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 17, 2012
RadiationMonochromator: Double-crystal, Si(111) liquid N2 cooled / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.906→106.739 Å / Num. all: 81984 / Num. obs: 81574 / % possible obs: 99.5 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.7 % / Rsym value: 0.11 / Net I/σ(I): 11.1
Reflection shellResolution: 1.906→1.912 Å / Redundancy: 3.7 % / Mean I/σ(I) obs: 2.9 / Num. unique all: 801 / Rsym value: 0.595 / % possible all: 99.9

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASERphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.906→65.331 Å / SU ML: 0.22 / σ(F): 1.07 / Phase error: 20.24 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2096 7760 5.06 %Random
Rwork0.1627 ---
obs0.165 81574 94.75 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 31.119 Å2 / ksol: 0.366 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-12.6629 Å20 Å2-1.3872 Å2
2--6.2396 Å20 Å2
3---0.4906 Å2
Refinement stepCycle: LAST / Resolution: 1.906→65.331 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7524 0 80 900 8504
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0067778
X-RAY DIFFRACTIONf_angle_d1.0210535
X-RAY DIFFRACTIONf_dihedral_angle_d12.372855
X-RAY DIFFRACTIONf_chiral_restr0.071146
X-RAY DIFFRACTIONf_plane_restr0.0051337
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.906-1.92750.30982320.25114765X-RAY DIFFRACTION93
1.9275-1.95010.31492830.24734827X-RAY DIFFRACTION93
1.9501-1.97390.28342900.22794736X-RAY DIFFRACTION94
1.9739-1.99890.28582200.22264760X-RAY DIFFRACTION94
1.9989-2.02520.28132530.21974904X-RAY DIFFRACTION94
2.0252-2.0530.25972550.21664765X-RAY DIFFRACTION94
2.053-2.08230.28112750.21334814X-RAY DIFFRACTION94
2.0823-2.11340.23832370.19994825X-RAY DIFFRACTION95
2.1134-2.14640.26242850.18924798X-RAY DIFFRACTION94
2.1464-2.18160.26932400.18684866X-RAY DIFFRACTION94
2.1816-2.21920.24152640.18134837X-RAY DIFFRACTION94
2.2192-2.25960.20492570.16894831X-RAY DIFFRACTION95
2.2596-2.3030.23252660.16784833X-RAY DIFFRACTION95
2.303-2.350.20642270.16874841X-RAY DIFFRACTION95
2.35-2.40120.19832550.15924866X-RAY DIFFRACTION95
2.4012-2.4570.23142620.16324869X-RAY DIFFRACTION95
2.457-2.51850.22222660.16294920X-RAY DIFFRACTION95
2.5185-2.58660.21152780.16874797X-RAY DIFFRACTION95
2.5866-2.66270.23452540.16654949X-RAY DIFFRACTION96
2.6627-2.74860.21982650.16714873X-RAY DIFFRACTION96
2.7486-2.84680.2432350.16434921X-RAY DIFFRACTION96
2.8468-2.96080.20122600.17044959X-RAY DIFFRACTION96
2.9608-3.09560.21462660.16084908X-RAY DIFFRACTION96
3.0956-3.25880.20332450.1514904X-RAY DIFFRACTION96
3.2588-3.46290.18372560.14284892X-RAY DIFFRACTION95
3.4629-3.73030.17122680.1414790X-RAY DIFFRACTION94
3.7303-4.10560.15863220.12234833X-RAY DIFFRACTION95
4.1056-4.69960.14272160.1124741X-RAY DIFFRACTION92
4.6996-5.92040.16852780.12534931X-RAY DIFFRACTION97
5.9204-65.36970.16732500.15294961X-RAY DIFFRACTION97
Refinement TLS params.Method: refined / Origin x: 13.3833 Å / Origin y: 1.2481 Å / Origin z: 22.6702 Å
111213212223313233
T-0.0201 Å2-0.012 Å2-0.008 Å2--0.015 Å20.0151 Å2---0.024 Å2
L0.0287 °20.0006 °2-0.0019 °2-0.0209 °20.0098 °2--0.0274 °2
S0.0297 Å °-0.0178 Å °-0.007 Å °-0.0271 Å °0.0129 Å °-0.0232 Å °-0.0032 Å °0.0304 Å °0.0698 Å °
Refinement TLS groupSelection details: ALL

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